Cell vaccines are prepared from tumor cell lines that are cultured in vitro. The vaccine product is designed to contain one or more antigens that are unique to cells; some preparations also contain “adjuvants” thought to enhance the immunogenicity of the preparation.
Whole cell vaccines have several advantages for tumor immunity. They are composed of a large array of antigens, identified ones as well as not yet defined ones, and they are relatively easy to produce. The inventors previously showed that an autologous vaccine of dinitrophenyl (DNP)-modified melanoma cells, improved disease-free (DFS) and overall survival (OS) in post-operative high risk adjuvant patients who successfully attained anti-melanoma reactivity as detected by positive delayed type hypersensitivity reactions to unmodified melanoma cells (Lotem et al., 2009). One drawback of the autologous vaccine is the fact that cancer patients often lack an available source of tumor for the growth of tumor cell lines. A vaccine derived from allogeneic tumor cell lines could overcome this obstacle. This approach led in the past to the production of an allogeneic vaccine that compared favorably with the adjuvant effect of maximally-tolerated doses of interferon alpha (Mitchell et al., 2007), with significantly lower treatment-related toxicity.
Most allogeneic vaccines used thus far did not take into consideration the need for HLA (human leukocyte antigen molecules) matching between the tumor of the donor and the recipient (Chapman et al., (2007). HLA antigens play a crucial role in presenting peptides derived from self and foreign proteins in a form that is recognized by T cells. Thus, matching the HLA phenotype of the donor cells and the recipient is essential for efficient cell-mediated cytotoxicity in response to vaccine treatment. In the absence of HLA compatibility, vaccines rely for their immune effect on the mediation of secondary antigen presenting cells (APC) to process and present antigens in conjunction with the host's HLA. Antigen presentation by APC may favor CD4 responses, inducing regulatory T cells side by side with helper T cell populations (Morelli et al., 2006). Nevertheless, it should be noted that APC presentation may also facilitate CD8 responses.
Various approaches for developing tumor cell vaccines have been disclosed. For example, EP2404614 discloses a composition for stimulating an immune response in patients having different types of cancer comprising a combination of allogeneic tumor cells and/or tumor stem cells that are selected on the basis of secreting at least one immunosuppressive agent, e.g., TGF-β, and that are genetically modified to reduce or inhibit the expression of said at least one immunosuppressive agent, and that collectively express a spectrum of tumor associated antigens, and a physiologically acceptable carrier.
US Patent Publication No. 2010/055136 discloses a composition for the treatment or prevention of a tumor, comprising: (i) allogeneic or xenogeneic tumor cells; (ii) a lysate of a syngeneic tumor cell; and (iii) a pharmaceutically acceptable excipient.
US Patent Publication No. 2010/119537 discloses a method of producing a protective immune response in a human subject comprising administering to the subject an effective amount of lung cancer cells transfected with a eukaryotic expression vector derived from the bovine papilloma virus comprising a nucleic acid encoding CD80 (B7.1) and with a eukaryotic expression vector derived from the bovine papilloma virus comprising a nucleic acid encoding an HLA antigen.
U.S. Pat. No. 5,882,654 discloses a pharmaceutically acceptable polyvalent melanoma cell composition for injection, the composition comprising viable cells of one or more allogeneic melanoma call lines which cells have been rendered incapable of proliferation in vivo and which provide to the composition an amount of melanoma associated antigens effective to stimulate an antitumor immune response, the composition including the specific melanoma associated antigens GD2 ganglioside, GM2 ganglioside, M-TAA, M-fetal antigen and M-urinary antigen in amounts effective to stimulate an immune response against each of said specific antigens.
WO9003183 discloses an immunotherapeutic melanoma tumor vaccine comprising: a melanoma cell lysate produced from allogeneic melanoma tumor cells; and an adjuvant comprising a refined detoxified endotoxin and at least one biological immunostimulant selected from the group consisting of mycobacterial cell wall skeleton, trehalose dimycolate, pyridine soluble extract of a microorganism, and mixtures thereof.
Initial attempts to develop allogeneic cell vaccines for clinical use in melanoma patients have been reported. Specifically, polyvalent melanoma whole cell vaccines have been evaluated (Morton et al., 1992; Morton et al., 2002; Barth et al., 1994; Bystryn et al., 1992). Hoon et al. report the survival data of melanoma patients receiving a polyvalent melanoma cell vaccine comprising three irradiated cell lines. The publication reports that expression of the HLA B35 by the recipient patients was correlated with a poor survival outcome following vaccination (Hoon et al., 1998). A genetically modified allogeneic cancer vaccine, GVAX, has been developed by Cell Genesys. GVAX is an allogeneic cancer vaccine composed of lethally irradiated whole cancer cells that are genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). This platform is currently undergoing multiple clinical trials. Initial clinical results with Canvaxin, a polyvalent, whole-cell vaccine derived from three melanoma cell lines were encouraging, demonstrating prolonged survival in a subset of patients receiving the vaccine (Morton et al. 1992, 2002). However, phase III study of Canvaxin versus Bacillus Calmette-Guerin (BCG) closed prematurely after interim analysis (Riker et al., 2007). Thus, additional means for improving the efficacy of tumor cell vaccines including melanoma cell vaccines are clearly required.
There remains an unmet medical need for providing improved immunotherapy for treatment of proliferative disorders, specifically metastatic cancer. Development of new and effective whole cell vaccines, and of assays useful for selecting patients that are likely benefit from treatment with such vaccines, would be highly advantageous.